Propionic acid derivatives

ABSTRACT

β-[Benzo(b)thienyl-3]propionic acid derivatives in the form of their amino esters (and salts thereof) are prepared. These compounds have spasmolytic, vasodilatatric, antiserotanic and local anaesthetic activity.

This is a division of application Ser. No. 150,747, filed June 7, 1971, now U.S. Pat. No. 3,865,842.

This invention relates to β-[benzo(b)thienyl-3] propionic acid derivatives and the amino esters of these derivatives.

The compounds of the invention correspond to the following formula: ##EQU1## wherein

R represents an allyl, phenyl, benzyl, thenyl, tetrahydrofurfuryl or tetrahydropyrannyl-methyl radical and

R' represents a hydrogen atom or the group ##EQU2## wherein

R₁ represents a hydrogen atom or a linear or branched alkyl having 1 to 3 carbon atoms

Am represents the radical of a dialkylamine of which the alkyls have 1 to 4 carbon atoms or the radical of an cyclic amine having 5, 6 or 7 members which may include a supplementary hetero atom, and

N IS 1 OR 2.

The cyclic amine radical may be particularly that of pyrrolidine, piperidine, cyclohexamethylene-imine or morpholine.

The invention includes the salts which give amino-esters with pharmaceutically acceptable mineral or organic acids as well as the quaternary ammonium derivatives of these amino-esters, and the racemic and optically active forms of the acids and amino-esters.

The derivatives of β[benzo(b)thienyl-3] propionic acid may be prepared, according to the invention, from 3-chloromethyl-benzo(b) thiophene by malonic synthesis.

One may work, in particular, in the following manner: the 3-chloromethyl-benzo (b) thiophene is condensed with a malonic ester carrying, in 2-position, the radical R (compound III) by warming to reflux in ethanol in the presence of sodium ethylate.

After hydrolysis in an aqueous hydrochloric acid medium there is obtained a malonic ester carrying in 2-position, as well as the radical R, the radical [benzo(b) thienyl-3] methyl (compound IV) which is extracted with diethyl ether and distilled.

By prolonged heating under reflux in a solution of potassium in benzyl alcohol, the malonic esters (IV) are saponified and decarboxylated. After dilution with water and acidification, there are obtained the β-[benzo(b)thienyl-3] propionic acids (Compounds I) which may be purified by distillation in vacuo and recrystallisation.

The malonic ester used is, for preference, ethyl malonate.

In this case the reaction scheme is the following: ##SPC1##

The aminated esters (compounds II) of the β-[benzo(b) thienyl-3] propionic acids (compounds I) may be prepared by heating the acids to reflux in isopropanol with the amino-alcohol chlorides of the formula ##EQU3## wherein R₁, n and Am have the meanings given above.

The amino esters are thus obtained in the form of their hydrochlorides. The amino-esters (bases) are oils.

To obtain them in the form of organic acid salts the hydrochloride may be treated in aqueous solution with soda, the amino-ester extracted with the aid of an organic solvent, the solvent eliminated in vacuo, the residue dissolved in acetone, 1.5 equivalents of the selected organic acid added and the mixture refluxed for 15 to 30 minutes. The salt crystallises on cooling.

The following Examples illustrate the present invention:

EXAMPLE 1

a. Allyl [(benzo(b) thienyl-3) methyl]malonate ethyl ester

A solution of 23 g of sodium and 200 g of 2-allyl malonate ethyl ester in 600 cc of absolute ethanol is heated to reflux for 1 hour. It is slightly cooled and a solution of 181.5 g of 3-chloromethyl-benzothiophene in 100 cc of absolute alcohol is poured in. It is heated to reflux, with stirring, for 17 hours. It is poured into 1 liter of water, acidified with hydrochloric acid and extracted with ether. It is dried over sodium sulphate, the solvent eliminated and it is distilled in vacuo. A yellow oil is obtained. B.Pt. ₅ = 240°-250°. Yield 70%.

b. α-allyl-β-[ (benzo(b)thienyl-3] propionic acid

A solution of 300 g of allyl [(benzo(b) thienyl-3)-methyl] malonate ethyl ester and 97 g of potassium in 3.5 liters of benzyl alcohol is heated to reflux for 15 hours. The solvent is distilled in vacuo, the residue poured into 2 liters of water, acidified with hydrochloric acid and extracted with benzene. It is dried over sodium sulphate, the solvent eliminated and the residue distilled in vacuo. A yellow oil is obtained. B.pt. ₃ = 215°. Yield 80%.

EXAMPLES 2-6

A. By operating as in Example 1(a) one obtains in the form of yellow distillable oils the malonic esters indicated below:

phenyl[ (benzo(b)thienyl-3)-methyl]malonate ethyl ester,

B.pt₁₂. = 235°-245° - Yield: 72%

benzyl[(benzo(b)thienyl-3)-methyl] malonate ethyl ester,

B.pt.₆ = 250°-260° - Yield: 75%

(thenyl-2')[(benzo(b)thienyl-3')-methyl]malonate ethyl ester,

B.pt₈. = 280°-290° - Yield: 80%

(tetrahydro-furfuryl)[ (benzo(b)thienyl-3')-methyl]malonate

ethyl ester, B.pt₅. = 238°-246° - Yield: 80%

(tetrahydropyrannyl-methyl)[ (benzo(b)thienyl-3)-methyl]

malonate ethyl ester - B.pt₅. = 247°-253° - Yield: 65%.

b. From the listed malonic esters, and operating as in Example 1(b) there are obtained the following β-[benzo(b)thienyl- 3]propionic acids in the form of distillable oils or solids:

α-phenyl β-[benzo(b)thienyl-3]propionic acid; white crystals; m.p 120°, B.p.₉ = 260°-263°; cristallisable in a mixture of 1/1 acetonitrile and hexane - Yield: 70%.

α-benzyl β-[benzo(b)thienyl-3] propionic acid; white solid m.p. 116° ; B.p.₅ = 245°-255° ; cristallisable in a mixture of 2 liters of hexane and 150 cc of ethyl acetate - Yield: 80 %.

α-(thenyl-2)β-[benzo(b)thienyl-3] propionic acid; white crystals; m.p. 85° ; b.p.₉ = 290°-300° ; cristallisable in a mixture (4/1) of hexane and ethyl acetate - Yield: 75 %.

α-tetrahydrofurfuryl β-[benzo(b)thienyl- 3] propionic acid; white crystals; m.p. 116° ; b.p. = 240°-243° ; cristallisable in a mixture (4/1) of hexane and ethyl acetate - Yield: 80%.

α-(tetrahydropyrannyl-methyl)β-[benzo(b)thienyl- 3] propionic acid; white crystals; m.p. 100° ; cristallisable in a mixture (1/2) of ethyl acetate and hexane - Yield: 50 %.

EXAMPLE 7 N,N-diethylamino ethyl ester of α-phenyl-β-[(benzo(b)thienyl- 3] propionic acid and its oxalate.

There is heated to reflux for 17 hours a solution of 5 g of α-phenyl-β-[benzo(b)thienyl- 3]propionic acid and 2.4 g of N,N-diethylamino-chloroethane in 60 cc isopropanol. It is evaporated to dryness in vacuo, the residue taken up in a saturated aqueous solution of sodium carbonate and extracted with chloroform. The solvent is dried over sodium sulphate and then eliminated. The residue is dissolved in 50 cc acetone, the solution is filtered and then added to a solution of 3 g oxalic acid in 20 cc acetone. It is heated to reflux for 30 minutes and separated after cooling. It is recrystallised in a mixture of 1/1 diethyl ether and absolute ethanol. White crystals are obtained. M.p. 110°. Yield 65 %.

In Tables I, II, III, IV and V set out below there are identified the amino ester salts of β-[benzo(b)thienyl-3] propionic acids prepared in a similar fashion, the salt of Example 7 being assigned the number 13.

                                      TABLE I                                      __________________________________________________________________________     No.                                                                               R.sup.1   Nature of the salt-                                                                       Melting                                                                              Yield                                                                               Solvent of                                               forming acid HY                                                                           Point °C                                                                      %    cristallisation                             __________________________________________________________________________     1  C.sub.2 H.sub.5                                                                (CH.sub.2).sub.2 --N∠                                                              citric acid                                                                               97    60   acetonitrile                                   C.sub.2 H.sub.5                                                             2  (CH.sub.2).sub.2 --                                                                      oxalic acid                                                                               98    65   acetonitrile                                3  (CH.sub.2).sub.2 --                                                                      citric acid                                                                               85    75   acetonitrile                                4  (CH.sub.2).sub.2 --N O                                                                   oxalic acid                                                                               110   70   acetonitrile                                5  (CH.sub.2).sub.2 --                                                                      oxalic acid                                                                               120   65   acetonitrile                                   CH.sub.3                                                                    6  (CH.sub.2).sub.3 --N∠                                                              oxalic acid                                                                               115   60   acetonitrile                                   CH.sub.3                                                                       C.sub.2 H.sub.5                                                             7  (CH.sub.2).sub.3 --N∠                                                              citric acid                                                                               85    70   acetonitrile (1)                               C.sub.2 H.sub.5                 plus ethyl ether (1)                        8  (CH.sub.2).sub.3 --                                                                      citric acid                                                                               86    75   acetonitrile                                9  (CH.sub.2).sub.3 --                                                                      oxalic acid                                                                               102   65   acetonitrile                                10 (CH.sub.2).sub.3 --                                                                      oxalic acid                                                                               100   60   acetonitrile (1)                                                               plus ethyl ether                                                               (1)                                         11 --CH--CH.sub.2 --                                                                        oxalic acid                                                                               92    65   acetonitrile                                   |                                                                     CH.sub.3                                                                    __________________________________________________________________________

                                      TABLE II                                     __________________________________________________________________________     No.                                                                                  R.sup.1   Nature of the salt                                                                       Melting                                                                              Yield                                                                              Solvent of                                                 forming acid HY                                                                          Point°C                                                                       70  cristallisation                            __________________________________________________________________________        CH.sub.3                                                                    12 (CH.sub.2).sub.2 -- N∠                                                                oxalic acid                                                                              150   70  acetonitrile (1)                              CH.sub.3                         plus ethyl ether (1)                          C.sub.2 H.sub.5                                                             13 (CH.sub.2).sub.2 -- N∠                                                                oxalic acid                                                                              110   65  absolute ethanol                              C.sub.2 H.sub.5                  (1) plus ethyl                                                                 ether (1)                                  14 (CH.sub.2).sub.2 --                                                                         citric acid                                                                               85   65  acetonitrile                               15 (CH.sub.2).sub.2 --                                                                         oxalic acid                                                                              130   70  absolute ethanol                                                               (1) plus ethyl                                                                 ether (1)                                  16 (CH.sub.2).sub.2 --                                                                         oxalic acid                                                                              135   75  ethyl alcohol 95%                          17 (CH.sub.2).sub.2 --                                                                         oxalic acid                                                                              140   70  absolute ethanol                                                               (1) plus ethyl                                                                 (1) plus ethyl                                                                 ether (1)                                     CH.sub.3                                                                    18 (CH.sub.2).sub.3 --N∠                                                                 oxalic acid                                                                              168   60  absolute ethanol (1)                          CH.sub.3                         plus ethyl ether (1)                          C.sub.2 H.sub.5                                                             19 (CH.sub.2).sub.3 --N∠                                                                 citric acid                                                                               95   65  acetonitrile                                  C.sub.2 H.sub.5                                                             20 (CH.sub.2).sub.3 --                                                                         oxalic acid                                                                              103   65  absolute ethanol                                                               (1) plus ethyl                                                                 ether (1)                                  21 (CH.sub.2).sub.3 --                                                                         oxalic acid                                                                              141   70  ethyl alcohol 95%                                                              (1) plus ethyl                                                                 ether (1)                                  22 (CH.sub.2).sub.3 --                                                                         oxalic acid                                                                              101   65  acetonitrile                               23 --CH--CH.sub.2 --                                                                           citric acid                                                                               90   70  acetonitrile (1)                              |                       plus ethyl ether                              CH.sub.3                         (1)                                        __________________________________________________________________________

                                      TABLE III                                    __________________________________________________________________________     No.                                                                                  R.sup.1   Nature of the salt                                                                       Melting                                                                              Yield                                                                              Solvent of                                                 forming acid HY                                                                          Point°C                                                                       %   cristallisation                            __________________________________________________________________________        CH.sub.3                                                                    24 (CH.sub.2).sub.2 --N∠                                                                 oxalic acid                                                                              133   75  acetonitrile (1)                              CH.sub.3                         + ethyl ether (1)                             C.sub.2 H.sub.5                                                             25 (CH.sub.2).sub.2 -- N∠                                                                citric acid                                                                              115   70  acetonitrile                                  C.sub.2 H.sub.5                                                             26 (CH.sub.2).sub.2 --                                                                         citric acid                                                                              100   60  acetonitrile                               27 (CH.sub.2).sub.2 --                                                                         citric acid                                                                               85   65  acetonitrile                               28 (CH.sub.2).sub.2 --                                                                         oxalic acid                                                                              136   70  acetonitrile                                  CH.sub.3                                                                    29 (CH.sub.2).sub.3 --N∠                                                                 oxalic acid                                                                              118   75  acetonitrile                                  CH.sub.3                                                                       C.sub.2 H.sub.5                                                             30 (CH.sub.2).sub.3 --N∠                                                                 citric acid                                                                               87   80  acetonitrile                                  C.sub.2 H.sub.5                                                             31 (CH.sub.2).sub.3 --                                                                         oxalic acid                                                                              113   75  acetonitrile (1)                                                               + ethyl other (1)                          32 (CH.sub.2).sub.3 --                                                                         citric acid                                                                               85   70  acetonitrile (1)                                                               + ethyl ether (1)                          33 (CH.sub.2).sub.3 --                                                                         oxalic acid                                                                              128   75  acetonitrile (1)                                                               + ethyl ether (1)                          34 CH--CH.sub.2 --                                                                             citric acid                                                                               80   65  acetonitrile                                  |                                                                     CH.sub.3                                                                    __________________________________________________________________________

                                      TABLE IV                                     __________________________________________________________________________     No.                                                                                  R.sup.1   Nature of the salt                                                                       Melting                                                                              Yield                                                                              Solvent of                                                 forming acid HY                                                                          Point °C                                                                      %   cristallisation                            __________________________________________________________________________        CH.sub.3                                                                    35 (CH.sub.2).sub.2 --N∠                                                                 oxalic acid                                                                              133   70  acetonitrile                                  CH.sub.3                                                                       C.sub.2 H.sub.5                                                             36 (CH.sub.2).sub.2 --N∠                                                                 citric acid                                                                              111   75  acetonitrile (1) +                            C.sub.2 H.sub.5                  ethyl ether (1)                            37 (CH.sub.2).sub.2 --                                                                         citric acid                                                                              105   70  acetonitrile (1)                                                               + ethyl ether (1)                          38 (CH.sub.2).sub.2 --                                                                         citric acid                                                                               88   80  acetonitrile (1)                                                               + ethyl ether (1)                          39 (CH.sub.2).sub.2 --                                                                         oxalic acid                                                                              160   65  acetonitrile (1)                                                               + ethyl ether (1)                          40 (CH.sub.2).sub.2 --                                                                         oxalic acid                                                                              133   70  absolute ethanol                                                               (1) + ethyl ether                                                              (1)                                           CH.sub.3                                                                    41 (CH.sub.2).sub.3 --N∠                                                                 oxalic acid                                                                              115   70  acetonitrile                                  CH.sub.3                                                                       C.sub.2 H.sub.5                                                             42 (CH.sub.2).sub.3 --N∠                                                                 citric acid                                                                               85   75  acetonitrile                                  C.sub.2 H.sub.5                                                             43 (CH.sub.2).sub.3 --                                                                         citric acid                                                                               85   80  acetonitrile (1)                                                               + ethyl ether (1)                          44 (CH.sub.2).sub.3 --N                                                                        oxalic acid                                                                              135   75  absolute ethanol                                                               (1) + ethyl ether                                                              (1)                                        45 (CH.sub.2).sub.3 --                                                                         citric acid                                                                               86   70  acetonitrile                               46 CH--CH.sub.2 --                                                                             citric acid                                                                               78   75  acetonitrile                                  |                                                                     CH.sub.3                                                                    __________________________________________________________________________

                                      TABLE V                                      __________________________________________________________________________     No.                                                                                 R.sup.1    Nature of the salt                                                                       Melting                                                                              Yield                                                                              Solvent of                                                 forming acid HY                                                                          Point °C                                                                      %   cristallisation                            __________________________________________________________________________        CH.sub.3                                                                    47 (CH.sub.2).sub.2 -- N∠                                                                oxalic acid                                                                              110   80  acetonitrile                                  CH.sub.3                                                                       C.sub.2 H.sub.5                                                             48 (CH.sub.2).sub.2 -- N∠                                                                citric acid                                                                               90   75  acetonitrile (1)                              C.sub.2 H.sub.5                  + ethyl ether (1)                          49 (CH.sub.2).sub.2 --                                                                         oxalic acid                                                                              120   75  acetonitrile                               50 (CH.sub.2).sub.2 --                                                                         oxalic acid                                                                              140   70  absolute ethanol                                                               (1) + ethyl                                                                    ether (1)                                  51 (CH.sub.2).sub.2 --                                                                         oxalic acid                                                                              124   75  acetonitrile                                  CH.sub.3                                                                    52 (CH.sub.2).sub.3 --N∠                                                                 oxalic acid                                                                               89   65  acetonitrile                                  CH.sub.3                                                                       C.sub.2 H.sub.5                                                             53 (CH.sub.2 ).sub.3 --N∠                                                                citric acid                                                                               83   75  acetonitrile                                  C.sub.2 H.sub.5                                                             54 (CH.sub.2).sub.3 --                                                                         oxalic acid                                                                              100   70  acetonitrile                               55 (CH.sub.2).sub.3 --                                                                         oxalic acid                                                                               98   75  acetonitrile                               56 (CH.sub.2).sub.3 --                                                                         oxalic acid                                                                               95   70  acetonitrile                               __________________________________________________________________________

The salts of amino ester derivatives of β-[benzo(b) thienyl-3]propionic acid have been made the subject of a pharmacological study showing their spasmolytic, vasodilatatric, antiserotonic and local anaesthetic activity.

1. Acute Toxicity

The acute toxicity of the amine ester derivatives of β-[ benzo(b)thienyl-3]propionic acid have been studied in the mouse by intraperitoneal and oral routes, the products being administered in an isotonic solution of sodium chloride, 0.9%, or in suspension in a dilute aqueous solution of carboxymethyl cellulose.

The calculation of the DL50 has been effected according to the method of MILLER and TAINTER (MILLER. L.C., TAINTER M.L. - Proc. Soc. Exptl. Biol. Med. 1944-57-261,264).

The results obtained are set out in Table IV for the compounds used by way of example.

                  TABLE VI                                                         ______________________________________                                         Acute toxicity in the mouse                                                    Compound                                                                               Route   Conc. g/100 ml                                                                              DL 50 (in mg/kg)                                  No.             of solution or                                                                 suspension                                                     ______________________________________                                         5       i.p     1.0          150 ± 17                                       6       i.p.    1.0          about 120                                         7       i.p.    2.0          210 ± 10                                               v.o.    5.0          1290 ± 80                                      11      i.p.    1.0          270 ± 59                                       37      i.p.    2.0          320 ± 21                                       42      i.p.    2.0          240 ± 18                                       43      i.p.    1.0          160 ± 11                                       49      i.p.    2.0          140 ± 9                                                v.o.    5.0          about 650                                         50      i.p.    1.0          122 ± 12                                       51      i.p.    1.0          121 ± 10                                       53      i.p.    1.0          145 ± 9                                                v.o.    5.0          1150 ± 78                                      54      i.p.    1.0          100 ± 12                                               v.o.    5.0          400 ± 27                                       55      i.p.    1.0          85 ± 12                                                v.o.    2.5          about 450                                         ______________________________________                                    

2. Spasmolytic Activity

The spasmolytic activity has been studied on isolated organs maintained in survival in a Tyrode solution aerated and heated to 38° for the rat duodenum, to 33° for the isolated ileum of the guinea pig, according to the technique of Magnus (Magnus R. Archiv. Ges. Physiol. - 1905 - 180 - 1.71).

a. To show activity of the papaverinic type, the contracturant used is barium chloride acting on the isolated rat duodenum.

The average activity of the substances studied has been effected by determining graphically their DE 30 and DE 50 these being expressed in μg for 20 ml of bath.

The results obtained with certain selected compounds taken by way of example and indicated in Table VII show that the derivatives of β-[benzo(b)thienyl-3]propionic acid possess a spasmolytic activity of papaverinic type.

This activity is equal or clearly superior to that of papaverine hydrochloride, this reference substance having a DE 50 varying generally between 60 and 80 μg/20 ml of bath in the experimental conditions defined above.

b. To show activity of atropinic type the contracturant used is acetylcholine chloride acting on the isolated ileum of the guinea-pig.

The average activity of the substances studied has been similarly researched by determining graphically their DE 30 and DE 50, these being expressed in μg/20 ml of bath.

The results obtained with certain compounds selected by way of example and indicated in Table VII show that the derivatives studied possess a weak atropinic activity, the DE 50 of atropine sulphate being equal to or less than 0.1μg/20 ml of bath in the experimental conditions defined above.

                  TABLE VII                                                        ______________________________________                                         Spasmolytic activity in vitro                                                  Compound                                                                               Spasmolytic activity                                                   No.     Papaverinic type                                                                               Atropinic type                                         DE 30         DE 50     DE 30     DE 50                                        ______________________________________                                         1       3.7       2.5                                                          2       12.0      23.0                                                         3       18.0      40.0                                                         5       13.0      20.0      95      180                                        6       9.0       20.0                                                         7       2.2       4.5       170     325                                        8       42.0      80.0      55      90                                         9       13.0      20.0                                                         10      7.2       13.0                                                         11      4.0       12.0                                                         12      24.0      50.0      50      100                                        13      13.0      45.0      30      42                                         14      18.0      35.0      90      140                                        15      45.0      70.0      26      45                                         16      38.0      110.0     225     450                                        18      8.0       20.0      22      35                                         19      11.5      25.0                                                         20      8.0       19.0      25      55                                         21      8.0       19.0      40      80                                         22      7.0       16.0                                                         23      3.1       7.0       50      140                                        24      10.0      25.0      90      200                                        25      9.0       18.0      60      120                                        26      5.5       12.0      50      140                                        27      6.0       12.0                                                         28      6.5       14.0      750     5000                                       29      4.0       8.5       45      100                                        30      6.0       13.0                                                         31      16.0      28.0      40      65                                         32      4.5       9.5                                                          33      4.0       8.5                                                          34      8.0       16.0                                                         36      8.5       20.0      14      28                                         37      6.8       13.0      50      80                                         38      6.0       16.0      95      200                                        39      43.0      80.0                                                         41      4.3       10.5      24      46                                         42      3.5       17.0      190     300                                        43      7.0       25.0                                                         44      5.5       8.0       30      70                                         45      14.0      27.0                                                         46      2.5       10.0      6.5     18                                         47      9.0       15.0                                                         48      6.0       25.0      10      18                                         49      1.6       3.7       21      28                                         50      5.0       12.0      48      70                                         51      3.5       6.5       61      95                                         52      8.0       14.0                                                         53      4.5       8.0       75      140                                        54      9.5       12.0      52      90                                         55      3.5       7.5                                                          56      10.0      16.0                                                         ______________________________________                                    

3. Vasodilatatric activity

a. The vaso-dialtatric activity with regard to the muscle fibre of vessels has been shown on the perfused isolated ear of the rabbit, after catheterism of the median artery, with the aid of a Tyrode solution maintained at ambient temperature.

The fall is registered with the aid of electronic apparatus including a Fleisch totalisator, the Tyrode solution being recovered at the ends of the "efferent" veins. It diminishes if one adds to the perfusion liquid a substance possessing vaso-constrictive properties such as adrenaline. The previous administration of a vaso-dilator opposes this diminution to an extent more or less marked according to the concentration used.

There has been observed, for certain of these derivatives, a vaso-dilatatric activity which, compared to that of papaverine hydrochloride, is of a similar intensity.

b. The vaso-dilatatric activity with regard to the coronary vessels has been shown on the isolated heart of the guinea-pig perfused according to the classic technique of LANGENDORFF, the coronary reduction being registered with the aid of electronic apparatus including a Fleisch totalisater.

There has been observed for certain derivatives selected by way of example a vaso-dilatatric activity comparable to that of papaverine hydrochloride. These derivatives equally oppose the vasoconstriction due to barium chloride added to the perfusion liquid.

4. Anti-serotonic activity

This has been researched in the rat by the technique of the acute oedema localised in the metatarsal region, provoked by the injection of 0.05 ml of a 0.01% solution of serotonine (sulphate of 5-hydroxy-tryptamine-creatinine) in an isotonic solution of sodium chloride.

The plethysmometric measurements of the paw having been subjected to the injection have been effected before, and at different times after, the injection of the serotonine.

The different results obtained with certain derivatives selected by way of example are presented in Table VIII and show a clear inhibition of the acute oedema localised consecutive to the intraplant injection of serotonine.

TABLE VIII

The derivatives to be studied have been administered by the oral route 30 minutes before the serotonine.

    Compound                                                                              Dose in  Conc.      average percentage                                  No.    mg/kg    g/100 ml   reduction inoedema after                                      of sus-                                                                        pension  1 hour     2 hours                                          ______________________________________                                         7      50       0.5        27.6     36.6                                       49     30       0.3        17.8     12.6                                       53     30       0.3        19.4     15.1                                              50       0.5        40.6     42.9                                       54     30       0.3        22.4     16.0                                              50       0.5        34.9     45.0                                       55     30       0.3        12.3     11.3                                              50       0.5        40.7     39.8                                       ______________________________________                                    

5. Local anaesthetic activity

The method of MOUKHTAR has been chosen to show the activity of the derivatives studied on conduction anaesthesia (A. MOUKHTAR, C.R. Soc. Biol. 1909-66-187,189).

The reference local anaesthetic substance used in the tests has in each case been procaine hydrochloride in 0.5% solution in an 0.9% isotonic solution of NaCl. The three concentrations used to study the local anaesthetic activity of the new derivatives are 0.50, 0.25 and 0.10%, the vehicle being the isotonic 0.9% solution of NaCl.

The average anaesthetic activity of the substances chosen is expressed comparatively to that of the reference product chosen, by calculating the ratio of the average number n of the stimulations necessary to obtain the appearance of the skin reflex in the case of the derivatives studied, to the average number (n') of the stimulation determined for the reference substance.

For example, in the experimental conditions defined above a substance possessing a local anaesthetic activity expressed by the number 1 has an activity equal to that of procaine hydrochloride.

The results obtained with certain selected compounds, by way of example, are indicated in Table IX and show a local anaesthetic activity comparable to that of procaine hydrochloride.

TABLE IX

The procaine hydrochloride and the derivatives studied are administered by the intradermal route at the rate of 0.20 ml per injection.

    __________________________________________________________________________     concentration in     average number of                                                                           local                                        g/100 ml             stimulations anaesthetic                                                                    activity                                     Compound                                                                            of the deriv-                                                                          of procaine                                                                            for the                                                                             for procaine                                         No.  ative studied                                                                          hydrochloride                                                                          deriva-                                                                             hydrochloride                                                             tive                                                                           studied                                                                        n    n'      n                                                                              n'                                           __________________________________________________________________________          0.50    0.50    29.5 30.5    1.0                                          7    0.25    0.50    18.9 33.9    0.6                                               0.10    0.50    12.2 36.0    0.3                                               0.50    0.50    33.2 27.2    1.2                                          53   0.25    0.50    29.1 29.5    1.0                                               0.10    0.50    14.2 30.5    0.5                                               0.50    0.50    31.4 29.2    1.1                                          54   0.25    0.50    25.7 33.7    0.8                                               0.10    0.50    16.7 28.2    0.6                                          __________________________________________________________________________

The derivatives of β-[benzo(b)thienyl-3]-propionic acid can be used in human therapy and in veterinary therapy by reason of their spasmolytic, vasodilataric, antiserotoninic and local anaesthetic properties.

The compounds which are particularly interesting in this regard are compounds Nos. 1, 5, 7, 11, 18, 23, 26, 32, 37, 46, 49, 50, 51, 53, 54, and 55 of Tables I to V.

The new drugs may be utilized in the treatment of spasmodic and painful conditions by digestive, biliary and urinary routes, of the arterio-venous system and the pelvic organs and in insufficient peripheral coronary and cerebral circulations.

The new derivatives may be presented for administration by oral, rectal or parenteral routes in man or animals, notably in association with excipients appropriate to these routes.

Thus, for example, they can be presented in the form of tablets, capsules, gelules, suppositories and injectable solutions. It will be understood that the invention includes pharmaceutical compositions which contain one or serveral of the new derivatives.

The daily dosage can, according to the case, vary from 50 to 600 mg.

The following is an example of a pharmaceutical composition:

    The citrate of the N,N-diethylamino propyl esters                              of x-allyl-β-[benzo(b)thienyl-3]propionic acid                                                       0.05g                                               Lactose                    0.100 g                                             Starch                     0.095 g                                             Magnesium stearate         0.005 g                                             to form a tablet weight 0.250 g.                                           

We claim as our invention:
 1. A β-[benzo(b)thienyl-3]propionic acid derivative of the formula ##SPC2##wherein R' is selected from the group consisting of ##EQU4##
 2. A derivative according to claim 1 in the form of an oxalic acid addition salt.
 3. A derivative according to claim 1 in the form of a citric acid addition salt. 